The Project Summary Psychostimulants are known to decrease food intake (hypophagia) while increasing drinking (polydipsia). Although the anorectic properties of stimulants are highly exploited in supplements marketed for weight loss, the specific mechanisms underlying the effects of stimulants on consummatory behaviors are not well understood. The aim of this proposal is to gain a better understanding of the neuronal circuitry underlying stimulant induced hypohpagia and polydipsia. Evolving evidence points to a role for dopamine and dopamine receptors in the striatum in regulating consummatory behaviors, and specifically dopamine D2 receptors (D2Rs) in the striatum. D2Rs are Gi/o- coupled receptors which exert inhibitory control over a number of neurochemically distinct populations of cells within the striatum including GABAergic medium spiny projection neurons, cholinergic interneurons and dopaminergic terminals emanating from the midbrain. Due to this ubiquitous expression and the poor selectivity of pharmacological agents, it has previously been impossible to study the roles of specific D2R subpopulations using pharmacological methods or global knockouts. Therefore, I will take advantage of recently generated conditional mice to selectively target D2R deletion in specific subpopulations of neurons. Recent evidence from our laboratory suggests that these transgenic manipulations result in differential locomotor behaviors and behavioral responses to stimulants. Thus, I hypothesize D2Rs localized to a specific subpopulation of striatal neurons will have disparate control over stimulant-induced hypophagia and polydipsia. To explore this idea I will profile the effects of various stimulants on food and water intake in wild type mice, as well as conditional knockouts for the three D2R-containing neuronal types described above (Aim 1). I will then use cell-specific manipulations of D2R-expressing neurons to determine their effect on stimulant-induced hypophagia and polydipsia. I will do this using optogenetics, chemogenetics and viral re-expression of D2Rs (Aim 2). Finally, I will use conventional and cutting edge technologies, such as viral tracing and CLARITY processing, in order to identify the circuitry underlying D2R modulation of stimulant induced polydipsia and hypophagia. Specifically, I will look at projections from the ventral striatum to the lateral hypothalamus, which are known to regulate food and water intake (Aim 3). The objective of these studies is to understand the role of D2Rs in the striatum in modulating stimulant- induced changes in food and water intake. In doing so, I will gain comprehensive training in genetic methods, circuitry mapping techniques and scientific inquiry. Better understanding of the neuronal circuitry underlying stimulant induced hypophagia and polydipsia will inform the development of anti-obesity drugs and provide insight into minimizing the anorexic side effects of psychostimulant medications used to treat ADHD.